Triptans

. . . Triptans are the most effective acute treatment for migraine and are recommended by evidence-based guidelines for the management of migraine . . .

Development

Improved understanding of the pathophysiology of migraine and the role of serotonin (5-hydroxytryptamine [5-HT]) receptors resulted in the development of a class of drugs that selectively bind to 5-HT_1B/1D receptors (triptans). The binding of triptans to these receptors aborts migraine attacks, which was a key milestone in the evolution of migraine therapy when discovered. Triptans represent the first class of drugs designed to relieve migraine symptoms by targeting the disease pathology. Unlike non-specific medications that increase patients’ tolerance to pain, nausea and associated symptoms, triptans act specifically via receptor-mediated binding in the central nervous system and its vascular system.

Mechanism of Action

The triptan drugs display highly selective and potent agonist activity at the 1B, 1D and 1F receptors and, to some extent, at the 1A 5-HT receptor. They have three main pharmacological actions:^[1-3]

• vasoconstriction of meningeal, dural, cerebral or pial vessels, mediated via stimulation of vascular 5-HT_1B receptors
• direct attenuation of excitability of cells in the trigeminal nuclei via stimulation of 5-HT_1B/1D receptors within the brainstem
• inhibition of dural neurogenic inflammation via stimulation of presynaptic 5-HT_1D receptors.

Efficacy

In the majority of patients, triptans take effect within 1-2 hours of dosing, with clinical data demonstrating efficacy as early as 10-15 minutes with specific formulations.^[4-6] Multiple clinical trials of triptans have demonstrated that treatment is most effective when taken early in the migraine attack, when the headache pain is still mild.^[7] Indeed, early treatment with a triptan (within 2-4 hours of onset) can abort migraine attacks in 80–90% of patients.^[8]

Safety

Data from clinical trials, post-marketing studies and extensive clinical use show that triptans are well tolerated, with most side effects being mild and transient.^[9-11] Reported side effects include:

• dizziness
• fatigue
• somnolence
• tingling sensations
• mild tightness in the throat or chest, and
• nausea.

When initiating therapy with triptans, physicians should discuss the potential for such side effects with patients, emphasising that they are not unusual or dangerous.

Triptans administered by subcutaneous injection may cause a higher number of side effects compared with other routes of administration, indicating the importance of selecting a drug formulation that is well tolerated by the patient.
Contraindications

Triptans are contraindicated in patients with cardiovascular disease, uncontrolled hypertension, and severe renal or hepatic impairment. However, extensive post-marketing experience has shown that the risk of coronary vasoconstriction with triptans is minimal.^[12]

Triptans should not be used in conjunction with other triptans or ergotamine derivatives, or with other medications that have the potential to interact with triptans. Current recommendations state that zolmitriptan, sumatriptan and rizatriptan should not be used with monoamine oxidase inhibitors. In addition, drugs that are primarily metabolised by the CYP3A4 route should not be used with eletriptan or any other CYP inhibitors.

For more specific information, please refer to the Prescribing Information of the individual product of interest.

Available agents

Sumatriptan was the first approved triptan for the acute treatment of migraine. However, due to the low bioavailability of sumatriptan oral tablets and the low patient acceptability of the injection formulation, second-generation triptans were developed to enhance pharmacological properties, clinical efficacy and tolerability.

The subsequent introduction of improved triptans has increased their use considerably, and these drugs are identified as the most effective acute treatment for migraine and recommended by all evidence-based guidelines for migraine management. A list of currently available triptans is shown in the table below:

*Not all agents will be available in all countries. Formulations and recommended dose may differ between countries; please consult your local Prescribing Information.

Zolmitriptan (Zomig)

Zomig was the first second-generation triptan to become available in clinical practice. The tablet formulation was approved for clinical use in migraine by the Food and Drug Administration in the USA and by regulatory authorities in many other countries in 1997. Zomig is now available in most countries worldwide.

Clinical trials show that Zomig rapidly relieves migraine headaches^{[13, 14]} and that its efficacy is consistent across a wide range of migraine subtypes.^{[15, 16]}

Three different formulations of Zomig are available:

• classic oral tablet
• orally disintegrating tablet (Rapimelt)
• nasal spray.

The availability of Zomig in a variety of different formulations enables migraine treatment to be customised to the patient's needs, preference and lifestyle.

To find out a lot more about Zomig, refer to the Triptans section on this site.

Important information:

• Zomig is indicated for the acute treatment of migraine with or without aura in adults. It should only be used where a clear diagnosis of migraine has been established and should not be administered to patients with hemiplegic or basilar-type migraine.
• The most common side effects seen in controlled clinical trials of Zomig are paraesthesia, asthenia, nausea, dizziness, pain, chest or neck tightness or heaviness, somnolence and warm sensation.
• As with other triptans, cardiovascular evaluation prior to the commencement of Zomig is recommended in patients in with risk factors for ischaemic heart diseas
• If the headache persists or returns after a single dose of ‘Zomig’, the dose may be repeated after two hours, but is not to exceed 10 mg within a 24-hour period.
• Please refer to the full Prescribing Information for Zomig.

References:
1. Ferrari MD. Migraine. Lancet 1998;351: 1043-51.
2. Ferrari MD, Saxena PR. On serotonin and migraine: a clinical and pharmacological review. Cephalalgia 1993;13: 151-65.
3. Goadsby PJ, Hoskin KL. Inhibition of trigeminal neurons by intravenous administration of the serotonin (5HT)1B/D receptor agonist zolmitriptan (311C90): are brain stem sites therapeutic target in migraine? Pain 1996;67: 355-9.
4. Dowson AJ, MacGregor EA, Purdy RA, Becker WJ, Green J, Levy SL. Zolmitriptan orally disintegrating tablet is effective in the acute treatment of migraine. Cephalalgia 2002;22: 101-6.
5. Gawel M, Aschoff J, May A, Charlesworth BR. Zolmitriptan 5 mg nasal spray: efficacy and onset of action in the acute treatment of migraine--results from phase 1 of the REALIZE Study. Headache 2005;45: 7-16.
6. Gawel M, Worthington I. Intranasal zolmitriptan. Expert Opin Pharmacother 2005;6: 1019-24.
7. Dowson AJ, Mathew NT, Pascual J. Review of clinical trials using early acute intervention with oral triptans for migraine management. Int J Clin Pract 2006;60: 698-706.
8. Cady R, Dodick DW. Diagnosis and treatment of migraine. Mayo Clin Proc 2002;77: 255-61.
9. Martin VT, Goldstein JA. Evaluating the safety and tolerability profile of acute treatments for migraine. Am J Med 2005;118 Suppl 1: 36S-44S.
10. Nappi G, Sandrini G, Sances G. Tolerability of the triptans: clinical implications. Drug Saf 2003;26: 93-107.
11. Tepper SJ, Millson D. Safety profile of the triptans. Expert Opin Drug Saf 2003;2: 123-32.
12. Rapoport AM, Tepper SJ, Bigal ME, Sheftell FD. The triptan formulations: how to match patients and products. CNS Drugs 2003;17: 431-47.
13. Rapoport AM, Bigal ME, Tepper SJ, Sheftell FD. Zolmitriptan (Zomig). Expert Rev Neurother 2004;4: 33-41.
14. Ryan R, Diamond S, Giammarco R, Aurora S, Reed R, Fletcher P. Efficacy of zolmitriptan at early time-points for the acute treatment of migraine and treatment of recurrence: a randomised, placebo-controlled trial. CNS Drugs 2000;13: 215-26.
15. Schoenen J, Sawyer J. Zolmitriptan (Zomig, 311C90), a novel dual central and peripheral 5HT1B/1D agonist: an overview of efficacy. Cephalalgia 1997;17 Suppl 18: 28-40.
16. Tuchman M, Edvinsson L, Geraud G, Korczyn A, Mauskop A, Pfaffenrath V. Zolmitriptan provides consistent migraine relief when used in the long-term. Curr Med Res Opin 1999;15: 272-81.